This proposal from the Department of Pediatrics, University of Colorado, seeks 5 year funding to establish a new program which investigates persistent pulmonary hypertension of the newborn (PPHN). PPHN is a relatively frequent (1:500 live births) disease of unknown origin associated with a high morbidity and mortality (25-50%) unless treated for days with invasive, expensive, and somewhat risky extracorporeal membrane oxygenation (ECMO). We propose to investigate initial insults (such as oxidant and hemodynamic stress) and mechanisms through which these insults lead to altered vasoreactivity and vascular remodeling (increased matrix, and vascular cell proliferation), clinical hallmarks of PPHN. Available for study are approximately 80-100 patients per year with established PPHN referred to The Children's Hospital, Denver, and 20 born to a high risk population at the University Hospital, where early detection procedures have been developed. Basic insights into mechanisms operating in PPHN will be from the patients, several animal models of neonatal pulmonary hypertension, and cellular and molecular studies. The data will allow early detection and interventions and better therapies aimed at effective vasodilation and restoration of depleted antioxidant defenses. The program will provide early detection, better treatment, and ultimately, prevention, of PPHN.